Celtic disease (CD) is a major but under diagnosis public health profile affecting 0.4-1 percent of the general U.S. Large prospective studies of high-risk children are needed to characterize genetic and environmental determinants of variable CD phenotypes and to develop optimal screening and prevention strategies. CD offers a model of the interplay between genetic, immunologic, and environmental factors in the etiology of autoimmune diseases. Genetic susceptibility to CD is largely restricted to the HLA-DR3, DQ2 and DR4, DQ8 haplotypes but non-HLA loci are also important. Autoantibodies to tissue transglutaminase (TG) are the best serological marker of CD; however, reliable assays for disease-specific T -cells reactive to the residues 57-73 of alpha-gliadin could greatly improve our ability to predict and stage CD. In contrast to most human autoimmune diseases, the critical antigen triggering CD is known. Elimination of dietary gliadin resolves the symptoms and prevents long-term complications, offering hope that often autoimmune diseases can be prevented or treated by modification of environmental factors. However, the diet if every difficult to adhere to and alternative forms of treatment of prevention is urgently needed. The proposed study will use three population-based cohorts of children at high risk of CD, with a large number of patients already positive for TG autoantibodies, that are available in our center in Denver to: The proposed study will use three population-based cohorts of children at high risk of CD, with a large number of patients already positive for TG autoantibodies, that are available in our center in Denver to: 1. Determine the incidence, environmental and genetic determinants, and the natural history of celiac disease through a prospective follow-up of three cohorts of high-risk children: a) Type I diabetic children (n=1,200), aged 0-18 years, examined annually; b) Non-diabetic first degree relatives of patients with type 1 diabetes (n=1,100), aged 0-18 years, examined annually; c) General population infants with high risk HLA-DR3/3, 5/7, 3/4 or 3/x genotypes (n=900) and those with lower risk HLA-DR4/X and 4/4 genotypes (n=700); these children are examined at ages 9, 15, 24 months, and yearly thereafter. 2. Develop and evaluate new bio-markers of CD risk, stage and activity: a) DQ2 and DQ8 tetramers specific for T-cells reactive to the consensus peptide of a-gliadin and extracted from intestinal biopsy specimens or peripheral blood obtained from TG positive patients and appropriate controls; peripheral blood obtained from TG positive patients and appropriate controls; b) DQ8 tetramers specific for T cells reactive to insulin, and GAD and extracted from intestinal biopsy specimens or peripheral blood of controls and patients with type 1 diabetes or islet autoantibodies in addition to CD or TG autoantibodies. 3. Initiate studies of novel interventions to prevent CD using TG inhibitors.